Our long term goal is to learn how inherited gene errors produce a specific pattern of epilepsy in the developing brain, and to provide an exact description of subsequent seizure-induced plasticity within affected neural networks. Generalized absence (petit mal) seizures of the spike and wave pattern comprise a major category of inherited epilepsy in children. The underlying basic neuronal excitability mechanisms, and the effects of spike-wave hypersynchrony on developing neural circuitry have not been clearly defined. The primary goal of this project is to examine a novel network abnormality identified in isolated thalamocortical brain slices of stargazer (stg) mutant mice with gene-linked spike-wave seizures. Two intracellular defects have been identified in vitro in adult mutant layer 4-5 cortical neurons: a spontaneous paroxysmal depolarizing shift (PDS) in normal saline solutions; and the absence of a post-PDS afterhyperpolarization (AHP). A specific defect in cortical NMDA receptor signaling is also present in the stg neocortex. We hypothesize: (1) that spike-wave discharges in the stg mutant arise from a cortical network excitability defect; (2) that distinct NMDA and GABAergic synaptic defects in stg neurons may be linked, respectively, to a primary defect of spontaneous bursting and a secondarily reduced AHP. Using intracellular recordings and molecular anatomy methods to study the mutant cortical neurons, we will examine specific hypotheses regarding the membrane and synaptic mechanisms underlying this network defect. We will explore its functional role in epileptogenesis by determining whether it arises developmentally as a primary cellular expression of the stg mutant locus, or secondarily as a product of seizure-induced neuroplasticity.
In specific aim 1, we will analyze membrane properties of control and mutant neurons to detect intrinsic defects in layer 4-5 pyramidal neurons, and quantify changes in the population of intrinsically bursting cells. We will isolate cortical neurons from thalamic projections to determine the minimal synaptic network required for the spontaneous network bursting.
In specific aim 2, we will explore intrinsic and synaptic mechanisms underlying the absence of post-PDS afterhyperpolarization.
In specific aim 3, we will examine the molecular basis for an abnormal response to NMDA antagonists.
In specific aim 4, we will examine the molecular basis for possible cortical GABA-A receptor defects.
In specific aim 5, we will examine the postnatal development of these properties relative to the onset of spike and wave seizures. These studies will directly test key hypotheses concerning basic mechanisms of generalized epilepsy, and the degree of long-term cellular and molecular neuroplasticity that may accompany early seizures of the spike-wave pattern.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029709-09
Application #
6126236
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Fureman, Brandy E
Project Start
1991-09-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
9
Fiscal Year
2000
Total Cost
$277,311
Indirect Cost
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Meyer, Jochen; Maheshwari, Atul; Noebels, Jeffrey et al. (2018) Asynchronous suppression of visual cortex during absence seizures in stargazer mice. Nat Commun 9:1938
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Maheshwari, Atul; Akbar, Abraham; Wang, Mai et al. (2017) Persistent aberrant cortical phase-amplitude coupling following seizure treatment in absence epilepsy models. J Physiol 595:7249-7260
Huang, Claire Yu-Mei; Zhang, Chuansheng; Ho, Tammy Szu-Yu et al. (2017) ?II Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function. J Neurosci 37:11311-11322
Lam, Alice D; Deck, Gina; Goldman, Alica et al. (2017) Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat Med 23:678-680
John Lin, Chia-Ching; Yu, Kwanha; Hatcher, Asante et al. (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396-405
Moyer, Jason T; Gnatkovsky, Vadym; Ono, Tomonori et al. (2017) Standards for data acquisition and software-based analysis of in vivo electroencephalography recordings from animals. A TASK1-WG5 report of the AES/ILAE Translational Task Force of the ILAE. Epilepsia 58 Suppl 4:53-67
Noebels, Jeffrey (2017) Precision physiology and rescue of brain ion channel disorders. J Gen Physiol 149:533-546

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